This drug may also cause the following symptoms that are related to drowsiness:

Kidney failure(common)

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Allopurinol should be discontinued at the first sign of skin rash or any other signs or symptoms suggestive of a hypersensitivity reaction. In some instances, a skin rash may be followed by more severe adverse reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity, and, rarely, death. Renal dysfunction increases the risk of allopurinol hypersensitivity.

Because allopurinol has been associated with drowsiness, patients should be cautious when engaging in activities where alertness is mandatory.

Some patients with preexisting renal disease or poor urate clearance have shown a rise in BUN during allopurinol therapy. Although the mechanism responsible for this has not been determined, patients with impaired renal function should be carefully monitored during the early stages of allopurinol use and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist. Renal failure in association with allopurinol use has been reported among patients with hyperuricemia secondary to neoplastic diseases. Concurrent conditions such as multiple myeloma and congestive myocardial disease were present among those patients whose renal dysfunctionincreased after allopurinol therapy was started. Renal failure is frequently observed with the use of allopurinol therapy. Albuminemia has been observed in patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis. Patients with decreased renal function require lower doses of allopurinol therapy than those with normal renal function. Periodic monitoring of renal function is recommended during the course of therapy.

A study of 13 patients who had pre- and post-clonidine cerebral blood flow (CBF) measured by nuclear scanning revealed that patients with an initially high pretreatment CBF tended to demonstrate decreased CBF after clonidine therapy.
Patients with traumatic spinal cord injury receiving clonidine may experience a delayed-onset of sedation regardless of the route of administration (i.e., intrathecal, intramuscular).

Epidural administration is contraindicated in patients receiving anticoagulant therapy, patients with bleeding diathesis, and in the presence of an injection site infection.

Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine can result in symptoms such as nervousness, agitation, headache, and confusion accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with clonidine, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptoms. An excessive rise in blood pressure following discontinuation of clonidine transdermal therapy can be reversed by administration of oral clonidine or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of clonidine transdermal therapy.

This drug may also cause the following symptoms that are related to drowsiness:

Drug withdrawal symptoms

Kidney failure

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Concurrent administration of gemfibrozil with cerivastatin is contraindicated due to the increased risk of myopathy and rhabdomyolysis. Gemfibrozil is considered contraindicated in patients with a history of gallbladder disease. Gemfibrozil decreases bile acid and increases cholesterol secretion thus increasing the lithogenicity of the bile and promoting gallstone formation. Gemfibrozil is contraindicated for use in patients with clinically significant renal or hepatic dysfunction, including patients with primary biliary cirrhosis or persistent hepatic abnormalities.

Musculoskeletal side effects of gemfibrozil include arthralgia, myopathy, myalgia, polyarthritis, and rhabdomyolysis. Myositis induced compartment syndrome is reported in one patient.

Gemfibrozil has been associated with severe myopathy and rhabdomyolysis. This is accompanied by elevations in creatine kinase, myoglobinuria, and proteinuria, as well as renal failure. Elevations in creatine kinase are more marked when gemfibrozil has been combined with another agent which is also capable of causing myopathy (i.e., HMG CoA reductase inhibitors, niacin). One review noted a case report with a creatine kinase level of 148,000 units/mL in a 79-year-old woman taking both gemfibrozil and lovastatin. Additional studies have confirmed that the combination of gemfibrozil and a HMG CoA reductase inhibitor increases the incidence and severity of myotoxicity.
Patients should be instructed to report symptoms of muscle pain, weakness, or tenderness. If such symptoms develop, creatine kinase should be measured, and, if elevated, gemfibrozil should be discontinued.
Gemfibrozil is associated with a higher incidence of myotoxicity (i.e., rhabdomyolysis) than fenofibrate when used in combination with any HMG CoA reductase inhibitor (statin). Fenofibrate is primarily metabolized by glucuronidation, whereas gemfibrozil undergoes extensive oxidative metabolism which results in higher plasma levels of statins. This pharmacokinetic difference may account for the differences in the rates of myotoxicity.

Renal side effects of gemfibrozil include acute renal failure associated with myositis and rhabdomyolysis.

Gemfibrozil is reported to cause rhabdomyolysis and subsequent renal failure. In one review, all patients in whom outcome was reported either significantly improved or completely recovered.

Verapamil is contraindicated in hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock, in sick sinus syndrome or second- or third-degree AV block in patients without a functioning artificial ventricular pacemaker, and in patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). In addition, oral verapamil is contraindicated in severe left ventricular dysfunction and intravenous verapamil is contraindicated in severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil therapy), in patients receiving intravenous beta-adrenergic blocking drugs, and in ventricular tachycardia. Intravenous verapamil is contraindicated within a few hours of administration of intravenous beta-adrenergic blocking agents since both may depress myocardial contractility and AV conduction. Intravenous verapamil is contraindicated in patients with wide complex ventricular tachycardia (QRS less than 0.12 sec) due to the risk of marked hemodynamic deterioration and ventricular fibrillation.

Significant hepatic and renal failure should not increase the effects of a single intravenous dose of verapamil but may prolong its duration. Repeated injections of intravenous verapamil in patients with significant hepatic and renal failure may lead to accumulation and an excessive pharmacologic effect of the drug. In general, multiple doses should be avoided in such patients. If repeated injections are essential, blood pressure and PR interval should be closely monitored and smaller repeat doses are recommended.

Increased intracranial pressure in patients with supratentorial tumors at the time of anesthesia induction has been reported with intravenous verapamil. Caution and appropriate monitoring are recommended.

Rare cases of hypertensive patients with chronic renal failure who developed acute oliguricrenal failure after receiving verapamil have been reported. These patients also developed symptomatic hypotension associated with slow cardiac arrhythmias.

Verapamil: an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. McTavish D, Sorkin EM Drugs 1989;38:19-76.

Drowsiness

Captopril and naproxen
in combination may cause the following symptom that is related to drowsiness:

Kidney failure

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Monitor blood pressure carefully if you are using both of these medications. Using these medications together may decrease the blood pressure-lowering effectiveness of the ACE inhibitor blood pressure medications and lead to increased blood pressure. Monitor blood pressure carefully if you are using both of these medications.

Dose adjustments may be necessary. Blood pressure should be monitored regularly when this drug combination is taken for long periods of time. People should be observed more closely around the time that the anti-inflammatory drug/s is started or stopped, or when the dose is changed. Blood tests for kidney function should be monitored regularly in individuals who take both of these medications.

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MONITOR: Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effects of ACE inhibitors. The proposed mechanism is NSAID-induced inhibition of renal prostaglandin synthesis, which results in unopposed pressor activity producing hypertension. In addition, NSAIDs can cause fluid retention, which also affects blood pressure. Some NSAIDs may also alter the pharmacokinetics of certain ACE inhibitors. For example, oxaprozin has been shown to reduce the systemic exposure (AUC) of enalapril and its active metabolite, enalaprilat.

MONITOR: Concomitant use of NSAIDs and ACE inhibitors may increase the risk of renal impairment, particularly in volume-depleted patients. Chronic use of NSAIDs alone may be associated with renal toxicities, including elevations in serum creatinine and BUN, tubular necrosis, glomerulitis, renal papillary necrosis, acute interstitial nephritis, nephrotic syndrome, and renal failure. Additionally, in patients with prerenal conditions whose renal perfusion may be dependent on the function of prostaglandins, NSAIDs may precipitate overt renal decompensation via a dose-related inhibition of prostaglandin synthesis. ACE inhibitors can further worsen renal function by blocking the effect of angiotensin II-mediated efferent arteriolar vasoconstriction, thereby decreasing glomerular filtration.

MANAGEMENT: Patients receiving ACE inhibitors who require prolonged (greater than 1 week) concomitant therapy with an NSAID should have blood pressure monitored more closely following initiation, discontinuation, or change of dosage of the NSAID. Renal function should also be evaluated periodically during prolonged coadministration. The interaction is not expected to occur with low doses (e.g., low-dose aspirin) or intermittent short-term administration of NSAIDs.

Captopril and allopurinol
in combination may cause the following symptom that is related to drowsiness:

Lethargy

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Patients who are taking captopril (captopril) and allopurinol (allopurinol) should be followed closely for signs of infection. Caution is advised if captopril (captopril) and allopurinol (allopurinol) are used together. People who are taking this drug combination should be followed closely. Serious side effects can occur with this drug combination. Cases of fatalities in individuals taking this drug combination have been reported in the medical literature. The following side effects have been mentioned in a case report: fast pulse/rapid heart rate that originates in the sinus node, nausea, hives, gout, breathing problems - tightening of the airways, significant decrease in blood pressure, generalized itching, thickening chest secretions, severe chest pain or bluish tone to fingers/toes due to lack of circulation. Some patients may experience the following side effects with the first dose of the enalapril: fast pulse/rapid heart rate that originates in the sinus node, nausea, hives, gout, breathing problems - tightening of the airways, significant decrease in blood pressure, generalized itching, thickening chest secretions, severe chest pain or bluish tone to fingers/toes due to lack of circulation. This medication combination may cause severe breathing problems due to closure of the airways.

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MONITOR CLOSELY: Coadministration of allopurinol with angiotensin converting enzyme (ACE) inhibitors has been associated with a risk of severe hypersensitivity reactions, neutropenia, agranulocytosis, and serious infections. The mechanism of interaction is unknown, but impaired renal function may be a predisposing factor. Case reports, albeit rare, have mostly involved captopril. Fever, myalgia, arthralgia, exfoliative dermatitis, and Stevens-Johnson syndrome (including one fatality) have been reported, with the latter occurring 3 to 5 weeks after initiation of allopurinol. In an isolated case involving enalapril, a man who had been receiving enalapril without incident developed generalized pruritus, urticaria, severe chest pain, severe nausea, peripheral cyanosis, hypotension, sinus tachycardia, and mild bronchospasm approximately 20 minutes after the first dose of allopurinol 100 mg prescribed for acute gout. Serial electrocardiograms and cardiac enzyme studies revealed evidence of acute myocardial infarction. Following recovery, the patient continued to take enalapril uneventfully without allopurinol. No pharmacokinetic interactions have been reported between allopurinol and ACE inhibitors. In a study of 12 healthy volunteers, allopurinol had no significant effect on the bioavailability of captopril.

MANAGEMENT: Caution is advised if allopurinol is prescribed in combination with an ACE inhibitor, particularly in the elderly and patients with renal impairment. Periodic monitoring of white blood cell counts is recommended. Patients should be advised to promptly discontinue these medications and seek medical attention if they develop dyspnea; throat constriction; swelling of the face, lips, or tongue; urticaria; rash; fever; arthralgia; or myalgia. Patients should also contact their physician if they notice signs of infection or experience fever, chills, sore throat, lethargy, body aches, or other flu-like symptoms.

Musculoskeletal side effects of simvastatin have included elevations in creatine kinase, myopathy, dermatomyositis, and rhabdomyolysis. Other musculoskeletal side effects reported with HMG-CoA reductase inhibitors have included arthralgia, myalgia, tendon rupture, and dermatomyositis.
In addition, some data have suggested that exposure to HMG-CoA reductase inhibitors is associated with a decreased risk of bone fractures in persons older than 50 years of age.

HMG-CoA reductase inhibitors (statins) have been associated with rare cases of severe myopathy and rhabdomyolysis, accompanied by increases in creatine kinase, myoglobinuria, proteinuria, and renal failure. Concomitant use with gemfibrozil (fibric acid derivatives), niacin, cyclosporine, erythromycin (macrolides) or azole antifungals may increase the incidence and severity of musculoskeletal side effects. Other variables associated with an increased risk of statin-induced myopathy include, advanced age, small body stature, female gender, renal and/or hepatic dysfunction, perioperative periods, hypothyroidism, diabetes mellitus, and alcoholism.
Milder forms of myotoxicity (i.e., myalgia) are commonly reported and occur in approximately 5% to 7% of patients taking a statin drug.
Patients should be instructed to report symptoms of muscle pain, weakness, or tenderness. If such symptoms develop, creatine kinase should be measured, and if elevated, simvastatin should be discontinued. The value of regular monitoring of creatine kinase is not known. In some studies, elevations in creatine kinase occurred in up to 5.2% of patients on simvastatin. In most cases, these elevations were mild, transient, and not associated with clinical symptoms.
At least six cases of simvastatin-induced rhabdomyolysis associated with concomitant use of a macrolide antibiotic (i.e., erythromycin, clarithromycin) have been reported. In all cases the patients had been receiving simvastatin routinely (40 to 80 mg/day) prior to short-term (7 to 10 days) macrolide therapy. The proposed mechanism of interaction is inhibition of CYP450 3A4 metabolism and/or P-glycoprotein transport of simvastatin. Symptoms included myalgia, muscle weakness, elevated serum creatine kinase levels, and in some patients elevated liver transaminase levels.
A rare case of simvastatin-induced bilateral leg compartment syndrome and myonecrosis developed in a patient with hypothyroidism after one month of therapy with simvastatin. Following withdrawal of simvastatin and emergency fasciotomies the patient recovered.

A 52-year-old male developed cutaneous necrotizing vasculitis, renal failure, and nephrotic syndrome following administration of naproxen 250 mg every 12 hours and dicloxacillin 250 mg every six hours for three days for the treatment of a blunt injury to the leg. Renal pathology was suggestive of a hypersensitivity angiitis. Symptoms resolved following discontinuation of naproxen.
Naproxen may impair the ability of the kidney to cope with low renal blood flow states due to inhibition of prostaglandin-dependent afferent arteriolar vasodilation. Renal function may be further compromised in patients with heart failure, hypovolemia, cirrhosis, nephrotic syndrome, or hypoalbuminemia. Additional risk factors for naproxen-induced renal insufficiency are advanced age and concomitant use of diuretics.
A case-control study suggested that patients who consumed 5000 or more pills containing NSAIDs during their lifetime may be at increased risk of end-stage renal disease.
Patients with reduced renal function may be at increased risk for renal side effects.

NSAIDs may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of administration. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with NSAIDs, the lowest effective dose should be used for the shortest duration possible. Prescribers and patients should remain vigilant for the development of such events, even in the absence of previous CV symptoms. Patients should be advised about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

Because of the potential to cause gastrointestinal bleeding, renal failure, high blood pressure, and heart failure, naproxen meets the Beers criteria as a medication that is potentially inappropriate for use in older adults.

Stop using levothyroxine and get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Call your doctor at once if you have any of these serious side effects:
headache;
sleep problems (insomnia);
nervous or irritable feeling;
fever, hot flashes, sweating;
changes in your menstrual periods;
appetite changes, weight changes;
Less serious side effects may include mild hair loss.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Cardiovascular side effects have included symptoms of palpitations, hypertension, tachycardia, and angina which may be exacerbated in patients with underlying cardiovascular disorders. Ischemic heart disease and significant effects on cardiac function including an increased incidence of premature ventricular beats, an increased left ventricular mass index, and enhanced left ventricular systolic function have been reported in clinical trials.

Cardiac function was evaluated in twenty patients requiring TSH suppression for either thyroid goiter or following thyroidectomy and radioactive iodine therapy for thyroid cancer and in twenty age- and sex-matched controls. TSH suppression was associated with an increased incidence of premature ventricular beats, an increased left ventricular mass index, and enhanced left ventricular systolic function. The clinical significance of these changes remains to be determined.
A 38-year-old female experienced with severe hypothyroidism experienced myxedema coma and cardiac ischemia coincident with levothyroxine therapy. After 3 months of levothyroxine therapy (initial dose: 12.5 mcg/d; maintenance dose: 125 mcg/d), all abnormal laboratory values associated with hypothyroidism returned to normal. However, three weeks after initiating treatment, the patient reported intermittent chest pains during the course of treatment, and a coronary artery angiogram revealed diffuse stenosis of all 3 branches. She underwent coronary artery bypass grafting, with subsequent improvement in coronary perfusion.

HydrALAZINE
may cause the following symptom that is related to drowsiness:

Lethargy(most common side effect)

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Note: Original Source for Medical ProfessionalsImmunologic side effects including the development of a lupus-like syndrome has been reported. It is more likely in patients who receive 400 mg or more of hydralazine per day, in female patients, or in patients who are slow acetylators. Of patients who receive less than 200 mg or 400 mg or more per day of hydralazine, 40% and 50%, respectively, develop a positive ANA titer, and up to 6% and 14%, respectively, develop a lupus-like syndrome.
The lupus syndrome may present as arthralgias (most common), myalgias, lethargy, malaise, a typical erythematous rash, weight loss, or dyspnea, but may be found incidentally in asymptomatic patients by urinalysis (proteinuria, hematuria), blood chemistry (elevated ESR, antinuclear antibody), or chest X-ray (interstitial lung disease, rare). Hypocomplementemia is an extremely rare finding in hydralazine-induced lupus.
Alternative therapy is recommended for patients who develop the clinical appearance of a lupus syndrome, sustained rises in the antinuclear antibody titer, or the presence of LE cells. The syndrome is reversible, but may take months to years to resolve.

Halkin, et al report a case in which use of both lovastatin and pravastatin on different occasions in the same patient led to reversible impotence. The impotence resolved within 2 weeks after discontinuation of the HMG-CoA reductase inhibitor.

Niacin
may cause the following symptom that is related to erectile dysfunction:

Problems involving sexual drive/performance

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Genitourinary complaints of decreasedsexual function have been reported in up to 3% and 22% of male patients who have taken unmodified and timed release niacin, respectively.

Gemfibrozil
may cause the following symptom that is related to genital problems:

Leydig cell tumors

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Many lipid-lowering drugs have been associated with tumor growth in rodents. Gemfibrozil has been specifically associated with liver tumors and Leydig cell tumors. Long-term clinical trials are needed to define the risk of cancer in humans.

Captopril and allopurinol
in combination may cause the following symptom that is related to gout-like arthritis:

Stevens-Johnson syndrome

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Patients who are taking captopril (captopril) and allopurinol (allopurinol) should be followed closely for signs of infection. Caution is advised if captopril (captopril) and allopurinol (allopurinol) are used together. People who are taking this drug combination should be followed closely. Serious side effects can occur with this drug combination. Cases of fatalities in individuals taking this drug combination have been reported in the medical literature. The following side effects have been mentioned in a case report: fast pulse/rapid heart rate that originates in the sinus node, nausea, hives, gout, breathing problems - tightening of the airways, significant decrease in blood pressure, generalized itching, thickening chest secretions, severe chest pain or bluish tone to fingers/toes due to lack of circulation. Some patients may experience the following side effects with the first dose of the enalapril: fast pulse/rapid heart rate that originates in the sinus node, nausea, hives, gout, breathing problems - tightening of the airways, significant decrease in blood pressure, generalized itching, thickening chest secretions, severe chest pain or bluish tone to fingers/toes due to lack of circulation. This medication combination may cause severe breathing problems due to closure of the airways.

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MONITOR CLOSELY: Coadministration of allopurinol with angiotensin converting enzyme (ACE) inhibitors has been associated with a risk of severe hypersensitivity reactions, neutropenia, agranulocytosis, and serious infections. The mechanism of interaction is unknown, but impaired renal function may be a predisposing factor. Case reports, albeit rare, have mostly involved captopril. Fever, myalgia, arthralgia, exfoliative dermatitis, and Stevens-Johnson syndrome (including one fatality) have been reported, with the latter occurring 3 to 5 weeks after initiation of allopurinol. In an isolated case involving enalapril, a man who had been receiving enalapril without incident developed generalized pruritus, urticaria, severe chest pain, severe nausea, peripheral cyanosis, hypotension, sinus tachycardia, and mild bronchospasm approximately 20 minutes after the first dose of allopurinol 100 mg prescribed for acute gout. Serial electrocardiograms and cardiac enzyme studies revealed evidence of acute myocardial infarction. Following recovery, the patient continued to take enalapril uneventfully without allopurinol. No pharmacokinetic interactions have been reported between allopurinol and ACE inhibitors. In a study of 12 healthy volunteers, allopurinol had no significant effect on the bioavailability of captopril.

MANAGEMENT: Caution is advised if allopurinol is prescribed in combination with an ACE inhibitor, particularly in the elderly and patients with renal impairment. Periodic monitoring of white blood cell counts is recommended. Patients should be advised to promptly discontinue these medications and seek medical attention if they develop dyspnea; throat constriction; swelling of the face, lips, or tongue; urticaria; rash; fever; arthralgia; or myalgia. Patients should also contact their physician if they notice signs of infection or experience fever, chills, sore throat, lethargy, body aches, or other flu-like symptoms.

Musculoskeletal side effects of simvastatin have included elevations in creatine kinase, myopathy, dermatomyositis, and rhabdomyolysis. Other musculoskeletal side effects reported with HMG-CoA reductase inhibitors have included arthralgia, myalgia, tendon rupture, and dermatomyositis.
In addition, some data have suggested that exposure to HMG-CoA reductase inhibitors is associated with a decreased risk of bone fractures in persons older than 50 years of age.

HMG-CoA reductase inhibitors (statins) have been associated with rare cases of severe myopathy and rhabdomyolysis, accompanied by increases in creatine kinase, myoglobinuria, proteinuria, and renal failure. Concomitant use with gemfibrozil (fibric acid derivatives), niacin, cyclosporine, erythromycin (macrolides) or azole antifungals may increase the incidence and severity of musculoskeletal side effects. Other variables associated with an increased risk of statin-induced myopathy include, advanced age, small body stature, female gender, renal and/or hepatic dysfunction, perioperative periods, hypothyroidism, diabetes mellitus, and alcoholism.
Milder forms of myotoxicity (i.e., myalgia) are commonly reported and occur in approximately 5% to 7% of patients taking a statin drug.
Patients should be instructed to report symptoms of muscle pain, weakness, or tenderness. If such symptoms develop, creatine kinase should be measured, and if elevated, simvastatin should be discontinued. The value of regular monitoring of creatine kinase is not known. In some studies, elevations in creatine kinase occurred in up to 5.2% of patients on simvastatin. In most cases, these elevations were mild, transient, and not associated with clinical symptoms.
At least six cases of simvastatin-induced rhabdomyolysis associated with concomitant use of a macrolide antibiotic (i.e., erythromycin, clarithromycin) have been reported. In all cases the patients had been receiving simvastatin routinely (40 to 80 mg/day) prior to short-term (7 to 10 days) macrolide therapy. The proposed mechanism of interaction is inhibition of CYP450 3A4 metabolism and/or P-glycoprotein transport of simvastatin. Symptoms included myalgia, muscle weakness, elevated serum creatine kinase levels, and in some patients elevated liver transaminase levels.
A rare case of simvastatin-induced bilateral leg compartment syndrome and myonecrosis developed in a patient with hypothyroidism after one month of therapy with simvastatin. Following withdrawal of simvastatin and emergency fasciotomies the patient recovered.

A 67-year-old woman with hypothyroidism, hypercalcemia, depression, and hypertension developed facial erythema, headaches, tremors, confusion and personality changes associated with a new positive ANA and anti-nRNP, and a skin biopsy consistent with lupus erythematosus while taking hydrochlorothiazide (HCTZ), levothyroxine, and amitriptyline. The eruption resolved upon discontinuation of HCTZ, but she later developed a higher ANA titer associated with symptomatic diffuse interstitial pulmonary infiltrates. She was successfully treated with corticosteroids.

HydrALAZINE
may cause the following symptoms that are related to gout-like arthritis:

Abnormal blood test - positive "rheumatoid factor".

Lupus erythematosis in less than 20% of people. This symptom may occur with doses of 400 milligram(s)

Lupus-like illness in 14% of people. This symptom may occur with doses between 200 and 400 milligram(s) per day

Joint swelling

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The incidence of hydralazine-induced systemic lupus erythematosus (SLE) is estimated at 5.4% for patients receiving 100 mg daily, 10.4% for those receiving 200 mg daily, and 10% to 20% for those receiving 400 mg or more daily. It should be noted that hydralazine-induced SLE has occurred at doses as low as 50 mg daily. Risk factors associated with development of hydralazine-induced SLE include slow acetylator status, HLA-DRw4 phenotype, female gender, high daily dose, therapy longer than 3 months, and a family history of autoimmune disease. Black patients appear to develop hydralazine-induced SLE less frequently than other populations. Musculoskeletal symptoms appear to be the most common clinical manifestation of hydralazine-induced SLE; however, it appears that any organ system can be involved. Laboratory findings that may aid in the diagnosis of hydralazine-induced SLE include antinuclear antibody (ANA), lupus erythematosus cells, rheumatoid factor, and antihistone antibodies.

Immunologic side effects including the development of a lupus-like syndrome has been reported. It is more likely in patients who receive 400 mg or more of hydralazine per day, in female patients, or in patients who are slow acetylators. Of patients who receive less than 200 mg or 400 mg or more per day of hydralazine, 40% and 50%, respectively, develop a positive ANA titer, and up to 6% and 14%, respectively, develop a lupus-like syndrome.
The lupus syndrome may present as arthralgias (most common), myalgias, lethargy, malaise, a typical erythematous rash, weight loss, or dyspnea, but may be found incidentally in asymptomatic patients by urinalysis (proteinuria, hematuria), blood chemistry (elevated ESR, antinuclear antibody), or chest X-ray (interstitial lung disease, rare). Hypocomplementemia is an extremely rare finding in hydralazine-induced lupus.
Alternative therapy is recommended for patients who develop the clinical appearance of a lupus syndrome, sustained rises in the antinuclear antibody titer, or the presence of LE cells. The syndrome is reversible, but may take months to years to resolve.

Because up to 20% of patients who receive 400 mg per day or more develop a systemic lupus erythematosus syndrome, some experts recommend checking a patient's acetylator status before giving higher doses. Up to 70% of "resistant" patients are fast acetylators, in whom the dose can be relatively safely increased.
Data suggest that hydralazine lupus may represent a unique hypersensitivity reaction in which antibodies to native DNA occur. These antibodies are believed to account for the clinical similarities between hydralazine-induced lupus and systemic lupus erythematosus.

Hydralazine may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis. In such patients, hydralazine should be discontinued unless the benefit-to-risk determination requires continued antihypertensive therapy with this drug. Symptoms and signs usually regress when the drug is discontinued but residual effects have been detected many years later.

A 46-year-old woman developed forearm edema, mild thenar atrophy, and skin hypopigmentation within three months after beginning clonidine for perimenopausal flushing. Electromyelography was consistent with carpal tunnel syndrome. At surgical decompression, a skin biopsy revealed changes consistent with immune-complex disease. The patient's signs and symptoms abated after physical therapy and discontinuation of clonidine.

Cardiovascular side effects have included hypotension and sinus and atrioventricular arrhythmias. Postural hypotension occurs in 2% of patients. Rebound hypertension (which may be worse than pretreatment values) can present as irritability, tremors, headache, increased salivation, and palpitations. Rebound hypertension may be minimized by gradual reduction of dosage over two to four days.
Hypotension with epidural clonidine has been reported in 45% of 38 patients in one study. Hypotension occurred more commonly in the first four days, in women, in lower weight patients, and those receiving higher dosages.
Other cardiovascular side effects have included sinus bradycardia in approximately 0.3% of patients. A rare case of sinus arrest associated with clonidine has been reported. Patients with preexisting sinus node dysfunction, patients who have developed bradycardia while taking other sympatholytic agents, patients who are on another sympatholytic agent, and patients with renal dysfunction are at increased risk of clonidine-associated sinus bradycardia. Clonidine may cause hypertension in some patients with idiopathic orthostatic hypotension, particularly those with autonomic nervous system dysfunction. There have also been reports of congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block, and arrhythmias), palpitations, Raynaud's phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

A 53-year-old man with diabetes mellitus, hypertension, and heart failure developed arthralgias, fever, and malaise associated with bilateral pleural effusions, elevated liver function tests, a pericardial rub, and elevated C-reactive protein. After other causes of systemic lupus erythematosus were ruled out, captopril was stopped, and these signs and symptoms resolved.
In a study of 78 patients who were treated with captopril for 11 months, 13 developed a positive antinuclear antibody titer. Only one of the 13, however, developed a serum sickness-like illness.

An increase in acute attacks of gout have been observed during the early stages of use of allopurinol, even when normal or subnormal serum uric acid levels have been reached. Accordingly, maintenance doses of colchicine generally should be given prophylactically when allopurinol therapy is started. The administration of colchicine or anti-inflammatory agents may be necessary to suppress gouty attacks in some instances. The gout attacks usually become shorter and less severe after several months of treatment. The mobilization of urates from tissue deposits which lead to fluctuations in the serum uric acid levels may be a possible explanation for these attacks. Even with adequate allopurinol treatment, it may require several months to deplete the uric acid pool adequately to achieve control of the acute attacks.

Some patients with preexisting renal disease or poor urate clearance have shown a rise in BUN during allopurinol therapy. Although the mechanism responsible for this has not been determined, patients with impaired renal function should be carefully monitored during the early stages of allopurinol use and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist. Renal failure in association with allopurinol use has been reported among patients with hyperuricemia secondary to neoplastic diseases. Concurrent conditions such as multiple myeloma and congestive myocardial disease were present among those patients whose renal dysfunctionincreased after allopurinol therapy was started. Renal failure is frequently observed with the use of allopurinol therapy. Albuminemia has been observed in patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis. Patients with decreased renal function require lower doses of allopurinol therapy than those with normal renal function. Periodic monitoring of renal function is recommended during the course of therapy.

Levothyroxine and simvastatin
in combination may cause the following symptom that is related to hearing loss:

Underactive thyroid gland

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The following side effects have been mentioned in a case report: underactive thyroid gland or increased tsh levels. No special actions appear to be necessary when taking these drugs at recommended doses. This drug interaction appears to be rare. The dose of levothyroxine (levothyroxine) may need to be adjusted if an interaction is suspected. The dose of hormone may need to be adjusted if an interaction is suspected. These side effects have only occured in a few individuals.

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Rarely, lovastatin and simvastatin have been reported to reduce the pharmacologic effects of thyroid hormone. The exact mechanism of interaction is unknown. In isolated case reports, patients stabilized on levothyroxine developed symptoms of hypothyroidism and/or elevated thyroid-stimulating hormone (TSH) levels following the addition of lovastatin or simvastatin. Discontinuation of the statin led to resolution of symptoms and normalization of TSH levels. In one case, the patient was subsequently prescribed pravastatin without any adverse effects on his thyroid status. No particular intervention should be necessary when lovastatin or simvastatin is prescribed to patients receiving thyroid hormone therapy, since the interaction appears to be extremely rare. However, thyroid hormone dosage may need to be adjusted if an interaction is suspected. Alternatively, a switch to a statin with a different metabolic profile such as fluvastatin, pravastatin, or rosuvastatin may help.

Levothyroxine
may cause the following symptoms that are related to hearing loss:

Coma caused by severely low thyroid hormone level(single case).

Underactive thyroid gland

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Thyroid hormones are not appropriate treatment for obesity or to aid in weight loss. Treatment of obesity in euthyroid patients with replacement dosages of thyroid hormones is ineffective. Serious or life-threatening toxicity may occur when thyroid hormones are given in larger doses, especially when given concomitantly with sympathomimetic amines used for their anorectic effects.

Levothyroxine is contraindicated in patients with untreated thyrotoxicosis of any etiology and in patients with acute myocardial infarction. Levothyroxine is also contraindicated in patients with uncorrected adrenal insufficiency. Increased requirements for adrenocortical hormone by tissue could precipitate an acute adrenal crisis. In patients with nontoxic diffuse goiter or nodular thyroid disease, particularly elderly patients or those with underlying cardiovascular disease, levothyroxine is contraindicated if the serum TSH level is already suppressed due to the risk of precipitating over thyrotoxicosis. If the serum TSH level is not suppressed, levothyroxine should be used cautiously in conjunction with careful monitoring of thyroid function for evidence of hyperthyroidism and clinical monitoring for potential associated adverse cardiovascular signs and symptoms of hyperthyroidism.
Unless associated with hypothyroidism, thyroid hormone is not appropriate treatment of male or female infertility.

Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.

Cardiovascular side effects have included symptoms of palpitations, hypertension, tachycardia, and angina which may be exacerbated in patients with underlying cardiovascular disorders. Ischemic heart disease and significant effects on cardiac function including an increased incidence of premature ventricular beats, an increased left ventricular mass index, and enhanced left ventricular systolic function have been reported in clinical trials.

Cardiac function was evaluated in twenty patients requiring TSH suppression for either thyroid goiter or following thyroidectomy and radioactive iodine therapy for thyroid cancer and in twenty age- and sex-matched controls. TSH suppression was associated with an increased incidence of premature ventricular beats, an increased left ventricular mass index, and enhanced left ventricular systolic function. The clinical significance of these changes remains to be determined.
A 38-year-old female experienced with severe hypothyroidism experienced myxedema coma and cardiac ischemia coincident with levothyroxine therapy. After 3 months of levothyroxine therapy (initial dose: 12.5 mcg/d; maintenance dose: 125 mcg/d), all abnormal laboratory values associated with hypothyroidism returned to normal. However, three weeks after initiating treatment, the patient reported intermittent chest pains during the course of treatment, and a coronary artery angiogram revealed diffuse stenosis of all 3 branches. She underwent coronary artery bypass grafting, with subsequent improvement in coronary perfusion.

Naproxen and hydrochlorothiazide
in combination may cause the following symptom that is related to heart disease due to high blood pressure:

High blood pressure

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This drug combination of can affect kidney function. The combination of naproxen (naproxen) and hydrochlorothiazide (hydrochlorothiazide) can cause low blood pressure. Monitor blood pressure carefully if you are using both of these medications. Contact your physician if you develop symptoms of heart failure including: shortness of breath, swelling in the ankles/legs, fatigue, lack of energy, loss of appetite, or nausea. The risk of the following side effects may be increased: congestive heart failure. The risk of developing (or worsening) congestive heart failure/weakened heart is increased in patients taking these medications. One published article suggested that the chance of developing congestive heart failure may be increased by using this drug combination people age 55 or older, 9.3 or older, 1,000 or older, 23.3 or older. The risk of developing (or worsening) congestive heart failure/weakened heart is increased in patients taking these medications people age 55 or older, 9.3 or older, 1,000 or older, 23.3 or older. Taking these two drugs together can increase the blood levels of a substance called "potassium". Check with your physician immediately for any signs of increased potassium including weakness, lack of energy, irregular heartbeat, confusion, or tingling or a feeling of heaviness in the arms or legs.

Drink lots of fluids and avoid becoming dehydrated while taking this medication combination. Follow kidney function closely with regular blood tests when taking this drug combination. Kidney function may be evaluated with certain blood tests including a "BUN" and "creatinine".

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MONITOR: Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics may adversely affect renal function due to NSAID inhibition of the renal synthesis of prostaglandins that help maintain renal perfusion in dehydrated states. The risk may be increased in patients on dietary sodium restriction. At the same time, hypotensive effect of the diuretics may be reduced because inhibition of prostaglandins can lead to unopposed pressor activity and, consequently, elevation in bloodpressure. Natriuretic and diuretic effects may also be reduced, as NSAIDs have been reported to cause sodium and water retention, which may account for the increased risk of congestive heart failure associated with the combination. One study showed an increase in the incidence density of congestive heart failure (in patients over 55 years of age) from 9.3 per 1,000 person-years in patients on diuretics to 23.3 per 1,000 person-years in patients on both diuretic and NSAID therapy. NSAIDs may also increase the risk of hyperkalemia associated with potassium-sparing diuretics.

MANAGEMENT: In patients receiving both diuretic and NSAID therapy, management consists of avoiding dehydration and carefully monitoring the patient's renal function and blood pressure. If renal insufficiency or hyperkalemia develops, both drugs should be discontinued until the condition is corrected.

Naproxen
may cause the following symptom that is related to heart disease due to high blood pressure:

High blood pressure

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NSAIDs may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of administration. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with NSAIDs, the lowest effective dose should be used for the shortest duration possible. Prescribers and patients should remain vigilant for the development of such events, even in the absence of previous CV symptoms. Patients should be advised about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

NSAIDs, including naproxen, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. NSAIDs, including naproxen, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Heart disease due to high blood pressure

Levothyroxine
may cause the following symptom that is related to heart disease due to high blood pressure:

Cardiovascular side effects have included symptoms of palpitations, hypertension, tachycardia, and angina which may be exacerbated in patients with underlying cardiovascular disorders. Ischemic heart disease and significant effects on cardiac function including an increased incidence of premature ventricular beats, an increased left ventricular mass index, and enhanced left ventricular systolic function have been reported in clinical trials.

Hydrochlorothiazide
may cause the following symptom that is related to heart disease due to high blood pressure:

High blood pressure (can occur as long as 18 months after starting/treatment with hydrochlorothiazide)

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Immunologic side effects are rare, and include case reports of allergic vasculitis and hemolytic anemia. There are numerous case reports of patients developing a rash histologically identical to subacute cutaneous lupus following HCTZ administration.

There are rare case reports of hydrochlorothiazide-induced immune hemolytic anemia. The following illustrates a fatal case:
A 53-year-old man with hypertension developed nausea, vomiting, diarrhea, and progressive anorexia and weakness associated with scleral icterus, anemia with spherocytosis, dark red urine with proteinuria, bilirubinuria, hemoglobinuria, and elevated lactic dehydrogenase levels 18 months after beginning hydrochlorothiazide and methyldopa. Haptoglobin was less than 50 mg per dl. Direct and indirect Coombs tests were positive. The patient died suddenly; autopsy revealed no obvious cause of death, left ventricular hypertrophy, and mild coronary atherosclerosis.

HydrALAZINE
may cause the following symptoms that are related to heart disease due to high blood pressure:

Pulmonary hypertension. This symptom may occur with a history of chronic obstructive pulmonary disease

Rapidly progressive glomerulonephritis(single study)

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Cardiovascular side effects are related to the vasodilatory properties of hydralazine. Reflex tachycardia is commonly observed. Palpitations, flushing, edema, or chest pain have been reported in less than 5% of patients. The use of hydralazine in patients with severe chronic heart failure has been associated with ischemia, including episodes of myocardial infarction.
In patients with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD), hydralazine may increase pulmonary artery hypertension, especially during periods of hypoxia. The use of hydralazine in these patients may, on rare occasions, result in profound hypotension, tachycardia, and even death.
Rare cases of bradycardia or cardiac tamponade (associated with hydralazine-induced lupus) have been reported. Hydralazine does not have a deleterious effect on the lipid profile, and, in fact, has been shown to decrease total and LDL cholesterol.

Provocation of ischemia in patients with compromised left ventricular systolic dysfunction may be due to the inability of hydralazine to decrease preload, or left ventricular filling pressures.
The mechanism of increased pulmonary hypertension in patients with PH or COPD is a decrease of systemic vascular resistance accompanied by an increase in cardiac output without a fall in the pulmonary vascular resistance. In case reports and small series of patients, the use of hydralazine in such patients resulted in palpitations, chest tightness, unchanged pulmonary vascular resistance, increased pulmonary artery pressure, decreased systemic vascular resistance, and increased heart rate and cardiac output. For this reason, if hydralazine must be used, many experts recommend hemodynamic monitoring during hydralazine therapy in such patients.

Renal side effects are common in idiopathic systemic lupus erythematosus; however, immune complex glomerulonephritis is rare in drug-induced lupus. Rare cases of rapidly progressive and focal glomerulonephritis associated with the hydralazine-induced lupus syndrome are often accompanied by anemia, a positive anti-DNA antibody titer, and a positive ANA titer.

In one study, rapidly progressive glomerulonephritis (RPGN) is described in 4 of 444 patients, all of whom were men who were treated for 5 to 11 years with daily doses of 100 to 250 mg. In three of the four cases, biopsy revealed a focal and segmental glomerular necrosis with crescents and positive immunofluorescence. The antinuclear antibody titer became positive in three. Renal function improved in all but one after the withdrawal of hydralazine and institution of corticosteroid therapy. A number of other cases of RPGN are reported. It appears to be far more common in patients who are slow acetylators.

Clonidine
may cause the following symptom that is related to heart disease due to high blood pressure:

High blood pressure (can occur as long as 6 weeks after starting/treatment with clonidine)

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Cardiovascular side effects have included hypotension and sinus and atrioventricular arrhythmias. Postural hypotension occurs in 2% of patients. Rebound hypertension (which may be worse than pretreatment values) can present as irritability, tremors, headache, increased salivation, and palpitations. Rebound hypertension may be minimized by gradual reduction of dosage over two to four days.
Hypotension with epidural clonidine has been reported in 45% of 38 patients in one study. Hypotension occurred more commonly in the first four days, in women, in lower weight patients, and those receiving higher dosages.
Other cardiovascular side effects have included sinus bradycardia in approximately 0.3% of patients. A rare case of sinus arrest associated with clonidine has been reported. Patients with preexisting sinus node dysfunction, patients who have developed bradycardia while taking other sympatholytic agents, patients who are on another sympatholytic agent, and patients with renal dysfunction are at increased risk of clonidine-associated sinus bradycardia. Clonidine may cause hypertension in some patients with idiopathic orthostatic hypotension, particularly those with autonomic nervous system dysfunction. There have also been reports of congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block, and arrhythmias), palpitations, Raynaud's phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

A case of sinus arrest associated with clonidine has been reported. A 65-year-old man with diabetes, hypertension and unexplained syncope developed more frequent syncope and dizziness associated with documented episodes of sinus arrest during the first week of clonidine therapy. The patient had no hypoglycemia or orthostatic changes. The syncope and dizziness resolved upon discontinuation of clonidine; continuous electrocardiographic monitoring revealed a gradual and complete disappearance of sinus pauses. Junctional bradycardia and AV heart block have also been reported.
Ventricular tachycardia (VT) relatively refractory to lidocaine, but responsive to intravenous phentolamine, has been associated with clonidine withdrawal (case report). The authors believe that the VT was probably produced by humoral or neural stimulation of unregulated myocardial alpha-adrenergic receptors.
Transdermal clonidine has been implicated with hypertension in a quadriplegic patient with a C4 spinal lesion. The proposed mechanism is predominance of clonidine's peripheral alpha-1 adrenergic effects due to the patient's autonomic dysfunction, resulting in vasoconstriction and hypertension.
Sinus bradycardia or other supraventricular bradyarrhythmias are more likely in patients with underlying renal dysfunction.
In one case report, severe hypotension occurred during separation from cardiopulmonary bypass in a patient given intrathecal clonidine. The patient responded to volume expansion and use of vasoconstrictors.

Endocrinologic side effects have been limited to rare cases of gynecomastia, hyperprolactinemia, or hyperglycemia.

A 68-year-old black man with hypertension, status post unilateral nephrectomy, was incidentally found to have 4+ proteinuria, 1+ glycosuria, new elevated blood glucose levels, and between 1.8 and 5.4 grams of protein per 24-hour urine collection within 6 weeks after starting clonidine. The signs and symptoms of diabetes and the nephrotic syndrome disappeared within five months after discontinuation of clonidine. Because of his solitary kidney, a renal biopsy was not performed.

Captopril
may cause the following symptom that is related to heart disease due to high blood pressure:

High blood pressure (can occur as long as a few hours after starting/treatment with the drug)

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Dermatologic side effects have included psoriasiform rashes, pemphigus-like lesions, angioedema of the face and mucous membranes, pityriasis-like eruptions, alopecia, exfoliative dermatitis, photosensitivity, bullous or lichenoid eruptions, and erythematous eruptions. Rarely, worsened Kaposi's sarcoma lesions, oncolysis, pemphigus vulgaris, and Henoch-Schonlein Purpura have been reported. A case of toxic epidermal necrolysis has also been reported.

A 70-year-old, heterosexual, HIV-negative man with hypertension developed Kaposi's sarcoma (KS) during captopril therapy. The lesions completely resolved within three months after discontinuation of captopril. In another case, a 70-year-old woman with seropositive rheumatoid arthritis and hypertension developed KS within eight months after starting captopril therapy. A full work-up, including HIV antibody testing, was negative. The lesions did not resolve, but became flat, brown, and non-indurated within 15 days after captopril was stopped.
A 47-year-old male was given captopril for hypertension and developed an erythematous eruption on both cheeks within a few hours following the first dose. Positive reactions were obtained during patch testing for captopril at a later time.

Immunologic side effects have rarely included lymphadenopathy, systemic lupus erythematosus, and Henoch-Schonlein Purpura. Serum sickness-like illness has been reported.

A 53-year-old man with diabetes mellitus, hypertension, and heart failure developed arthralgias, fever, and malaise associated with bilateral pleural effusions, elevated liver function tests, a pericardial rub, and elevated C-reactive protein. After other causes of systemic lupus erythematosus were ruled out, captopril was stopped, and these signs and symptoms resolved.
In a study of 78 patients who were treated with captopril for 11 months, 13 developed a positive antinuclear antibody titer. Only one of the 13, however, developed a serum sickness-like illness.

This drug may also cause the following symptoms that are related to numbness or tingling:

Nerve damage (common)

Numbness/tingling in hands/feet (common)

Numbness/tingling in the arms or legs (common)

Numbness

Peripheral neuropathy

Vasculitis

Burning, prickling, tickling or tingling (uncommon)

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Nervous system side effects including peripheral neuropathy is dose-related and is more common in slow acetylators. The neuropathy usually first presents as paresthesias, numbness, and tingling in the extremities. It is probably the result of pyridoxine deficiency, perhaps because formation of a pyridoxal-hydralazine complex inactivates the coenzyme, and can, therefore, be treated by administration of pyridoxine. Headache or dizziness have been reported in approximately 5% of patients.

A 61-year-old man with hypertension developed ataxia, numbness, and lower extremity weakness approximately six months after beginning hydralazine (up to 300 mg per day) and reserpine therapy. The neuropathy partially resolved after reduction of the hydralazine dosage to 60 mg daily. A complete evaluation revealed that this man was a slow acetylator of hydralazine.

This drug may also cause the following symptoms that are related to numbness or tingling:

Burning, prickling, tickling or tingling in less than 1% of people

Skin tingling

Stroke

Vasculitis

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Musculoskeletal side effects have included myalgia (up to 1.1%) and bizarre perceptual symptoms most closely described as cold extremities. Muscle fatigue has been reported with intravenous verapamil. Arthralgia (with rash) and muscle cramps have been reported during open trials/postmarketing experience.

Three case reports have been found by one practitioner. In each case, unusual symptoms of cold extremities and paresthesias without objective evidence of a neuromuscular or cardiac etiology were described. The symptoms resolved upon discontinuation and, in each case, recurred upon drug rechallenge.

Antineutrophil cytoplasmic antibodies (ANCA) against human neutrophil elastase as well as against myeloperoxidase were documented in a 47-year-old man who developed vasculitis during allopurinol therapy for gout. Clinical improvement and decline in antibodies were noted upon discontinuation of allopurinol.

Renal side effects have included crystalluria and stone formation as well as elevations in blood urea nitrogen. Acute interstitial nephritis due to hypersensitivity and granulomatous nephritis have also been reported.

Naproxen
may cause the following symptom that is related to numbness or tingling:

Stroke caused by blockage of the arteries that supply blood to the brain

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NSAIDs may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of administration. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with NSAIDs, the lowest effective dose should be used for the shortest duration possible. Prescribers and patients should remain vigilant for the development of such events, even in the absence of previous CV symptoms. Patients should be advised about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

Numbness or tingling ("pins and needles")

Clonidine
may cause the following symptoms that are related to numbness or tingling:

Autonomic neuropathy.

Stroke(rare). This symptom may occur when the drug is stopped or dose is decreased

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Cardiovascular side effects have included hypotension and sinus and atrioventricular arrhythmias. Postural hypotension occurs in 2% of patients. Rebound hypertension (which may be worse than pretreatment values) can present as irritability, tremors, headache, increased salivation, and palpitations. Rebound hypertension may be minimized by gradual reduction of dosage over two to four days.
Hypotension with epidural clonidine has been reported in 45% of 38 patients in one study. Hypotension occurred more commonly in the first four days, in women, in lower weight patients, and those receiving higher dosages.
Other cardiovascular side effects have included sinus bradycardia in approximately 0.3% of patients. A rare case of sinus arrest associated with clonidine has been reported. Patients with preexisting sinus node dysfunction, patients who have developed bradycardia while taking other sympatholytic agents, patients who are on another sympatholytic agent, and patients with renal dysfunction are at increased risk of clonidine-associated sinus bradycardia. Clonidine may cause hypertension in some patients with idiopathic orthostatic hypotension, particularly those with autonomic nervous system dysfunction. There have also been reports of congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block, and arrhythmias), palpitations, Raynaud's phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

A case of sinus arrest associated with clonidine has been reported. A 65-year-old man with diabetes, hypertension and unexplained syncope developed more frequent syncope and dizziness associated with documented episodes of sinus arrest during the first week of clonidine therapy. The patient had no hypoglycemia or orthostatic changes. The syncope and dizziness resolved upon discontinuation of clonidine; continuous electrocardiographic monitoring revealed a gradual and complete disappearance of sinus pauses. Junctional bradycardia and AV heart block have also been reported.
Ventricular tachycardia (VT) relatively refractory to lidocaine, but responsive to intravenous phentolamine, has been associated with clonidine withdrawal (case report). The authors believe that the VT was probably produced by humoral or neural stimulation of unregulated myocardial alpha-adrenergic receptors.
Transdermal clonidine has been implicated with hypertension in a quadriplegic patient with a C4 spinal lesion. The proposed mechanism is predominance of clonidine's peripheral alpha-1 adrenergic effects due to the patient's autonomic dysfunction, resulting in vasoconstriction and hypertension.
Sinus bradycardia or other supraventricular bradyarrhythmias are more likely in patients with underlying renal dysfunction.
In one case report, severe hypotension occurred during separation from cardiopulmonary bypass in a patient given intrathecal clonidine. The patient responded to volume expansion and use of vasoconstrictors.

Epidural administration is contraindicated in patients receiving anticoagulant therapy, patients with bleeding diathesis, and in the presence of an injection site infection.

Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine can result in symptoms such as nervousness, agitation, headache, and confusion accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with clonidine, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptoms. An excessive rise in blood pressure following discontinuation of clonidine transdermal therapy can be reversed by administration of oral clonidine or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of clonidine transdermal therapy.

A 57-year-old man with hypertension and moderate alcohol use developed a sensorimotor loss associated with a cerebral spinal fluid pleocytosis three months after starting captopril therapy. A complete work-up was otherwise unremarkable. The patient eventually required mechanical ventilation, at which time captopril was discontinued. The syndrome resolved completely over the next six weeks. Nerve conduction velocity and electromyography findings were consistent with a demyelinatingneuropathy of the Guillain-Barre type.
A 75-year-old man with hypertension and heart failure developed a shuffling gait, resting tremors, mask face, and cogwheel rigidity several days after beginning captopril therapy. A full work-up was unremarkable. The parkinsonian symptoms resolved after captopril was discontinued.

REFERENCE +

Comparison of the safety and efficacy of delapril with captopril in outpatients with congestive heart failure. Fuchs W Am J Cardiol 1995;75:f29-36.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Stop taking naproxen and seek medical attention or call your doctor at once if you have any of these serious side effects:
chest pain, weakness, shortness of breath, slurred speech, problems with vision or balance;
black, bloody, or tarry stools;
coughing up blood or vomit that looks like coffee grounds;
swelling or rapid weight gain;
urinating less than usual or not at all;
nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
fever, sore throat, and headache with a severe blistering, peeling, and red skin rash;
bruising, severe tingling, numbness, pain, muscle weakness; or
fever, headache, neck stiffness, chills, increased sensitivity to light, purple spots on the skin, and/or seizure (convulsions).
Less serious side effects may include:
upset stomach, mildheartburn or stomach pain, diarrhea, constipation;
bloating, gas;
dizziness, headache, nervousness;
skin itching or rash;
blurred vision; or
ringing in your ears.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In one study, rapidly progressive glomerulonephritis (RPGN) is described in 4 of 444 patients, all of whom were men who were treated for 5 to 11 years with daily doses of 100 to 250 mg. In three of the four cases, biopsy revealed a focal and segmental glomerular necrosis with crescents and positive immunofluorescence. The antinuclear antibody titer became positive in three. Renal function improved in all but one after the withdrawal of hydralazine and institution of corticosteroid therapy. A number of other cases of RPGN are reported. It appears to be far more common in patients who are slow acetylators.

Hydralazine may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis. In such patients, hydralazine should be discontinued unless the benefit-to-risk determination requires continued antihypertensive therapy with this drug. Symptoms and signs usually regress when the drug is discontinued but residual effects have been detected many years later.

Swelling of the hands or feet

Naproxen and hydrochlorothiazide
in combination may cause the following symptom that is related to swelling of the hands or feet:

Congestive heart failure

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This drug combination of can affect kidney function. The combination of naproxen (naproxen) and hydrochlorothiazide (hydrochlorothiazide) can cause low blood pressure. Monitor blood pressure carefully if you are using both of these medications. Contact your physician if you develop symptoms of heart failure including: shortness of breath, swelling in the ankles/legs, fatigue, lack of energy, loss of appetite, or nausea. The risk of the following side effects may be increased: congestive heart failure. The risk of developing (or worsening) congestive heart failure/weakened heart is increased in patients taking these medications. One published article suggested that the chance of developing congestive heart failure may be increased by using this drug combination people age 55 or older, 9.3 or older, 1,000 or older, 23.3 or older. The risk of developing (or worsening) congestive heart failure/weakened heart is increased in patients taking these medications people age 55 or older, 9.3 or older, 1,000 or older, 23.3 or older. Taking these two drugs together can increase the blood levels of a substance called "potassium". Check with your physician immediately for any signs of increased potassium including weakness, lack of energy, irregular heartbeat, confusion, or tingling or a feeling of heaviness in the arms or legs.

Drink lots of fluids and avoid becoming dehydrated while taking this medication combination. Follow kidney function closely with regular blood tests when taking this drug combination. Kidney function may be evaluated with certain blood tests including a "BUN" and "creatinine".

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MONITOR: Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics may adversely affect renal function due to NSAID inhibition of the renal synthesis of prostaglandins that help maintain renal perfusion in dehydrated states. The risk may be increased in patients on dietary sodium restriction. At the same time, hypotensive effect of the diuretics may be reduced because inhibition of prostaglandins can lead to unopposed pressor activity and, consequently, elevation in blood pressure. Natriuretic and diuretic effects may also be reduced, as NSAIDs have been reported to cause sodium and water retention, which may account for the increased risk of congestive heart failure associated with the combination. One study showed an increase in the incidence density of congestive heart failure (in patients over 55 years of age) from 9.3 per 1,000 person-years in patients on diuretics to 23.3 per 1,000 person-years in patients on both diuretic and NSAID therapy. NSAIDs may also increase the risk of hyperkalemia associated with potassium-sparing diuretics.

MANAGEMENT: In patients receiving both diuretic and NSAID therapy, management consists of avoiding dehydration and carefully monitoring the patient's renal function and blood pressure. If renal insufficiency or hyperkalemia develops, both drugs should be discontinued until the condition is corrected.

Verapamil
may cause the following symptoms that are related to swelling of the hands or feet:

Congestive heart failure. This symptom may occur with a history of heart failure/weakened heart

Swelling of the legs or arms in less than 3.7% of people

Swollen ankles in less than 1.4% of people

Irregular heartbeat - atrial fibrillation

Worsening of congestive heart failure

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Other side effects have included flu syndrome (up to 3.7%), peripheral edema (up to 3.7%), edema (up to 3%), pain (up to 2.4%), fatigue (1.7%), accidental injury (up to 1.5%), ankleedema (up to 1.4%), and flushing (up to 0.8%). Asthenia has been reported during open trials/postmarketing experience.

CHF or pulmonary edema may be particularly important in patients with poor left ventricular function.
Various conduction disturbances have been reported with verapamil therapy, including bradycardia, AV block, first-, second-, third-degree heart block, and left bundle branch block.
One study of patients with the Wolff-Parkinson-White syndrome (WPW) has shown that patients with a history of WPW complicated by atrial fibrillation and a history of reciprocating tachycardias with rapid conduction over an accessory pathway during atrial fibrillation are more susceptible to ventricular fibrillation after verapamil than those without a history of a rapid ventricular response. A small series of patients with WPW complicated by atrial fibrillation and a rapid ventricular response who developed cardiac arrest within 1 to 10 minutes after receiving intravenous verapamil has been reported.
The mechanism by which verapamil may enhance the ventricular rate response to atrial fibrillation is not known. Verapamil may directly shorten the refractory period of the accessory pathway or cause reflex tachycardia indirectly by causing peripheral vasodilation.

Verapamil is contraindicated in hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock, in sick sinus syndrome or second- or third-degree AV block in patients without a functioning artificial ventricular pacemaker, and in patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). In addition, oral verapamil is contraindicated in severe left ventricular dysfunction and intravenous verapamil is contraindicated in severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil therapy), in patients receiving intravenous beta-adrenergic blocking drugs, and in ventricular tachycardia. Intravenous verapamil is contraindicated within a few hours of administration of intravenous beta-adrenergic blocking agents since both may depress myocardial contractility and AV conduction. Intravenous verapamil is contraindicated in patients with wide complex ventricular tachycardia (QRS less than 0.12 sec) due to the risk of marked hemodynamic deterioration and ventricular fibrillation.

Verapamil has a negative inotropic effect, which in most patients is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4954 patients primarily with immediate release verapamil, 1.8% developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30%) or moderate to severe symptoms of heart failure and in patients with any degree of ventricular dysfunction if they are receiving beta-blockers. Patients with milder ventricular dysfunction should, if possible, be controlled with digitalis and/or diuretics prior to initiation of verapamil.

Musculoskeletal side effects of simvastatin have included elevations in creatine kinase, myopathy, dermatomyositis, and rhabdomyolysis. Other musculoskeletal side effects reported with HMG-CoA reductase inhibitors have included arthralgia, myalgia, tendon rupture, and dermatomyositis.
In addition, some data have suggested that exposure to HMG-CoA reductase inhibitors is associated with a decreased risk of bone fractures in persons older than 50 years of age.

HMG-CoA reductase inhibitors (statins) have been associated with rare cases of severe myopathy and rhabdomyolysis, accompanied by increases in creatine kinase, myoglobinuria, proteinuria, and renal failure. Concomitant use with gemfibrozil (fibric acid derivatives), niacin, cyclosporine, erythromycin (macrolides) or azole antifungals may increase the incidence and severity of musculoskeletal side effects. Other variables associated with an increased risk of statin-induced myopathy include, advanced age, small body stature, female gender, renal and/or hepatic dysfunction, perioperative periods, hypothyroidism, diabetes mellitus, and alcoholism.
Milder forms of myotoxicity (i.e., myalgia) are commonly reported and occur in approximately 5% to 7% of patients taking a statin drug.
Patients should be instructed to report symptoms of muscle pain, weakness, or tenderness. If such symptoms develop, creatine kinase should be measured, and if elevated, simvastatin should be discontinued. The value of regular monitoring of creatine kinase is not known. In some studies, elevations in creatine kinase occurred in up to 5.2% of patients on simvastatin. In most cases, these elevations were mild, transient, and not associated with clinical symptoms.
At least six cases of simvastatin-induced rhabdomyolysis associated with concomitant use of a macrolide antibiotic (i.e., erythromycin, clarithromycin) have been reported. In all cases the patients had been receiving simvastatin routinely (40 to 80 mg/day) prior to short-term (7 to 10 days) macrolide therapy. The proposed mechanism of interaction is inhibition of CYP450 3A4 metabolism and/or P-glycoprotein transport of simvastatin. Symptoms included myalgia, muscle weakness, elevated serum creatine kinase levels, and in some patients elevated liver transaminase levels.
A rare case of simvastatin-induced bilateral leg compartment syndrome and myonecrosis developed in a patient with hypothyroidism after one month of therapy with simvastatin. Following withdrawal of simvastatin and emergency fasciotomies the patient recovered.

Cardiovascular side effects generally have been rare. Transient tachycardia, palpitations, atrial fibrillation, orthostasis, syncope, hypotension, and dizziness have been reported. The Coronary Drug Project (1975) reported a significant increase in cardiac arrhythmias associated with the use of niacin; some experts consider preexisting arrhythmias or angina pectoris contraindications to its use.
Niacin has been shown to increase plasma homocysteine levels. Homocysteine is an independent risk factor for arterial occlusive disease. Clinical implications of these increases and the influence of folic acid supplementation as a means to decrease homocysteine levels remain to be determined.

Naproxen
may cause the following symptoms that are related to swelling of the hands or feet:

Angioedema. Especially in people with allergic reaction to drugs

Swelling of the legs or arms in 3% to 9% of people

Fixed drug eruption(rare)

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NSAIDs may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of administration. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with NSAIDs, the lowest effective dose should be used for the shortest duration possible. Prescribers and patients should remain vigilant for the development of such events, even in the absence of previous CV symptoms. Patients should be advised about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

Patients with a hypersensitivity (angioedema, bronchospasm, urticaria, or rhinitis) to aspirin or other nonsteroidal anti-inflammatory agents (NSAIDs) may be cross sensitive to naproxen. Patients with the "triad" of asthma, nasal polyps, and aspirin or other NSAID hypersensitivity are at particular risk, and should consult their health care professional before taking products containing naprosyn. Both types of reactions have the potential of being fatal. The use of naproxen is considered contraindicated in these patients.

Naproxen is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. Patients with a hypersensitivity (angioedema, bronchospasm, urticaria, or rhinitis) to aspirin or other NSAIDs may be cross sensitive to naproxen. Patients with the "triad" of asthma, nasal polyps, and aspirin or other NSAID hypersensitivity are at particular risk. Both types of reactions have the potential of being fatal. The use of naproxen is considered contraindicated in these patients.

Peripheral edema has been observed in some patients receiving naproxen. Sodium containing naproxen tablets (approximately 1 mEq/250 mg naproxen) and suspension (39 mg (1.5 mEq) per each 125 mg of naproxen) should be used with caution in patients with fluid restriction, hypertension, or heart failure.

Cardiovascular side effects have included peripheral edema (3% to 9%) and palpitations (3%). Blood pressure may be elevated by naproxen, which may have clinical relevance in patients with comorbid illnesses. Dyspnea has been reported in patients receiving controlled release naproxen. An increased risk of cardiovascular events has been observed in preliminary study results from a clinical trial conducted by the National Institute of Aging evaluating the use of NSAIDs in patients at risk of developing Alzheimer's disease.

Cardiovascular side effects have included hypotension and sinus and atrioventricular arrhythmias. Postural hypotension occurs in 2% of patients. Rebound hypertension (which may be worse than pretreatment values) can present as irritability, tremors, headache, increased salivation, and palpitations. Rebound hypertension may be minimized by gradual reduction of dosage over two to four days.
Hypotension with epidural clonidine has been reported in 45% of 38 patients in one study. Hypotension occurred more commonly in the first four days, in women, in lower weight patients, and those receiving higher dosages.
Other cardiovascular side effects have included sinus bradycardia in approximately 0.3% of patients. A rare case of sinus arrest associated with clonidine has been reported. Patients with preexisting sinus node dysfunction, patients who have developed bradycardia while taking other sympatholytic agents, patients who are on another sympatholytic agent, and patients with renal dysfunction are at increased risk of clonidine-associated sinus bradycardia. Clonidine may cause hypertension in some patients with idiopathic orthostatic hypotension, particularly those with autonomic nervous system dysfunction. There have also been reports of congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block, and arrhythmias), palpitations, Raynaud's phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

Angiotensin converting enzyme (ACE) inhibitor use during pregnancy can cause injury and even death to the developing fetus. When used during the second and third trimesters of pregnancy, ACE inhibitors have been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Exposure to ACE inhibitors during the first trimester of pregnancy has been associated with prematurity, intrauterine growth retardation, patent ductus arteriosus, other structural cardiac malformations, and neurological malformations. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. If no alternative to ACE inhibitor therapy is available, patients should be made aware of the risks to their fetuses and the intra-amniotic environment should be evaluated by serial ultrasound examinations. If oligohydramnios develops, captopril should be discontinued unless it is considered life-saving for the mother. Depending on the week of pregnancy, contraction stress testing, a non-stress test, or biophysical profiling may be appropriate. Oligohydramnios may not show until after the fetus has suffered irreversible injury.

Anaphylactoid reactions have occurred in patients receiving ACE inhibitor therapy during desensitization treatment with hymenoptera venom, and in some patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.
In controlled trials, ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients.

Immunologic side effects have rarely included lymphadenopathy, systemic lupus erythematosus, and Henoch-Schonlein Purpura. Serum sickness-like illness has been reported.

A 53-year-old man with diabetes mellitus, hypertension, and heart failure developed arthralgias, fever, and malaise associated with bilateral pleural effusions, elevated liver function tests, a pericardial rub, and elevated C-reactive protein. After other causes of systemic lupus erythematosus were ruled out, captopril was stopped, and these signs and symptoms resolved.
In a study of 78 patients who were treated with captopril for 11 months, 13 developed a positive antinuclear antibody titer. Only one of the 13, however, developed a serum sickness-like illness.

Risk factors for the development of captopril-induced renal insufficiency are hypovolemia, hypotension, hyponatremia, concomitant use of other potentially nephrotoxic medications, and renal artery stenosis.
Proteinuria associated with captopril therapy is more likely in patients with renal insufficiency.
Captopril-induced hypotension may cause decreased renal blood flow and glomerular filtration in some patients. In addition, captopril may cause an interstitial nephritis (usually associated with rash, eosinophilia, fever, and azotemia), or a membranous glomerulopathy. The histological findings of membranous glomerulonephritis in some patients who have proteinuria suggest the possibility of an immune-complex glomerulopathy. These findings are similar to other cases of drug-induced glomerulopathy.

Swelling of the hands or feet

Allopurinol
may cause the following symptom that is related to swelling of the hands or feet:

Glomerulonephritis

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Allopurinol should be discontinued at the first sign of skin rash or any other signs or symptoms suggestive of a hypersensitivity reaction. In some instances, a skin rash may be followed by more severe adverse reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity, and, rarely, death. Renal dysfunction increases the risk of allopurinol hypersensitivity.

Some patients with preexisting renal disease or poor urate clearance have shown a rise in BUN during allopurinol therapy. Although the mechanism responsible for this has not been determined, patients with impaired renal function should be carefully monitored during the early stages of allopurinol use and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist. Renal failure in association with allopurinol use has been reported among patients with hyperuricemia secondary to neoplastic diseases. Concurrent conditions such as multiple myeloma and congestive myocardial disease were present among those patients whose renal dysfunctionincreased after allopurinol therapy was started. Renal failure is frequently observed with the use of allopurinol therapy. Albuminemia has been observed in patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis. Patients with decreased renal function require lower doses of allopurinol therapy than those with normal renal function. Periodic monitoring of renal function is recommended during the course of therapy.

Swelling of the hands or feet

Acetaminophen
may cause the following symptom that is related to swelling of the hands or feet:

Respiratory side effects have included upper respiratory infection (up to 5.4%), pharyngitis (up to 3%), sinusitis (up to 3%), rhinitis (up to 2.7%), and dyspnea (up to 1.4%). Extremely rare cases of respiratory arrest have been associated with the use of intravenous verapamil. The mechanism is unknown. An acute asthma attack associated with sustained-release verapamil has been reported. Dyspnea has also been reported during open trials/postmarketing experience.

Simvastatin is contraindicated in patients with active liver disease or with unexplained elevations in liver function tests. Simvastatin is a prodrug which must first be metabolized by hepatic microsomal enzymes to active compounds. In patients with active liver disease, simvastatin efficacy may be reduced. In addition, simvastatin is associated with elevations in liver function tests. Safety in patients with active liver disease or with unexplained elevations in liver function tests is unknown.

Rhabdomyolysis with acute renal failure secondary to myoglobinuria has been associated with simvastatin and other HMG-CoA reductase inhibitors. Simvastatin should be used cautiously, if at all, in patients who are at risk of developing renal failure from rhabdomyolysis (for example, patients with severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders, and uncontrolled seizures).
The risk of myopathy/rhabdomyolysis is dose related and is increased by concomitant use of simvastatin with potent Inhibitors of CYP450 3A4 as well as cyclosporine or danazol, particularly with higher doses of simvastatin. Use of simvastatin concomitantly with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, amiodarone, verapamil, niacin (doses greater than or equal to 1 gram/day), or large quantities of grapefruit juice (greater than 1 quart daily) should be avoided. Predisposing factors include advanced age (greater than or equal to 65), uncontrolled hypothyroidism, and renal impairment. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitantmedicationwith cyclosporine, danazol, or gemfibrozil. The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitantmedicationwith amiodarone or verapamil. The benefits of the use of simvastatin in patients receiving cyclosporine or danazol should be carefully weighed against the risks of these combinations. The combined use of simvastatin with gemfibrozil should be avoided unless the benefits are likely to outweigh the risks of the combination.

Endocrine side effects of HMG-CoA reductase inhibitors have included hypospermia, gynecomastia, and thyroid function abnormalities. In addition, acid maltase deficiency (the genetic disorder also referred to as Pompe's Disease) has been revealed following simvastatin therapy in at least one presymptomatic patient.

Naproxen
may cause the following symptoms that are related to throbbing headache:

Aseptic meningitis.

Headache

Stroke caused by blockage of the arteries that supply blood to the brain. This symptom can lead to fatalities in severe cases

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Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Stop taking naproxen and seek medical attention or call your doctor at once if you have any of these serious side effects:
chest pain, weakness, shortness of breath, slurred speech, problems with vision or balance;
black, bloody, or tarry stools;
coughing up blood or vomit that looks like coffee grounds;
swelling or rapid weight gain;
urinating less than usual or not at all;
nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
fever, sore throat, and headache with a severe blistering, peeling, and red skin rash;
bruising, severe tingling, numbness, pain, muscle weakness; or
fever, headache, neck stiffness, chills, increased sensitivity to light, purple spots on the skin, and/or seizure (convulsions).
Less serious side effects may include:
upset stomach, mildheartburn or stomach pain, diarrhea, constipation;
bloating, gas;
dizziness, headache, nervousness;
skin itching or rash;
blurred vision; or
ringing in your ears.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

NSAIDs may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of administration. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with NSAIDs, the lowest effective dose should be used for the shortest duration possible. Prescribers and patients should remain vigilant for the development of such events, even in the absence of previous CV symptoms. Patients should be advised about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

Levothyroxine
may cause the following symptom that is related to throbbing headache:

Headache

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Stop using levothyroxine and get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Call your doctor at once if you have any of these serious side effects:
headache;
sleep problems (insomnia);
nervous or irritable feeling;
fever, hot flashes, sweating;
changes in your menstrual periods;
appetite changes, weight changes;
Less serious side effects may include mild hair loss.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Throbbing headache

Hydrochlorothiazide
may cause the following symptom that is related to throbbing headache:

Headache (single case)

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Dermatologic reactions include case reports of erythema annular centrifugum, acute eczematous dermatitis, and morbilliform and leukocytoclastic vasculitis. Thiazides may induce phototoxic dermatitis. In addition, a rare, distinct entity with clinical and laboratory features indistinguishable from those of subacute cutaneous lupus erythematosus is associated with HCTZ.

A 67-year-old woman with hypothyroidism, hypercalcemia, depression, and hypertension developed facial erythema, headaches, tremors, confusion and personality changes associated with a new positive ANA and anti-nRNP, and a skin biopsy consistent with lupus erythematosus while taking hydrochlorothiazide (HCTZ), levothyroxine, and amitriptyline. The eruption resolved upon discontinuation of HCTZ, but she later developed a higher ANA titer associated with symptomatic diffuse interstitial pulmonary infiltrates. She was successfully treated with corticosteroids.

HydrALAZINE
may cause the following symptoms that are related to throbbing headache:

Glomerulonephritis(rare).

Headache in 5% of people

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Nervous system side effects including peripheral neuropathy is dose-related and is more common in slow acetylators. The neuropathy usually first presents as paresthesias, numbness, and tingling in the extremities. It is probably the result of pyridoxine deficiency, perhaps because formation of a pyridoxal-hydralazine complex inactivates the coenzyme, and can, therefore, be treated by administration of pyridoxine. Headache or dizziness have been reported in approximately 5% of patients.

Hydralazine may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis. In such patients, hydralazine should be discontinued unless the benefit-to-risk determination requires continued antihypertensive therapy with this drug. Symptoms and signs usually regress when the drug is discontinued but residual effects have been detected many years later.

Clonidine
may cause the following symptoms that are related to throbbing headache:

Headache.

Stroke(rare). This symptom may occur when the drug is stopped or dose is decreased

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Epidural administration is contraindicated in patients receiving anticoagulant therapy, patients with bleeding diathesis, and in the presence of an injection site infection.

Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine can result in symptoms such as nervousness, agitation, headache, and confusion accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with clonidine, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptoms. An excessive rise in blood pressure following discontinuation of clonidine transdermal therapy can be reversed by administration of oral clonidine or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of clonidine transdermal therapy.

Cardiovascular side effects have included hypotension and sinus and atrioventricular arrhythmias. Postural hypotension occurs in 2% of patients. Rebound hypertension (which may be worse than pretreatment values) can present as irritability, tremors, headache, increased salivation, and palpitations. Rebound hypertension may be minimized by gradual reduction of dosage over two to four days.
Hypotension with epidural clonidine has been reported in 45% of 38 patients in one study. Hypotension occurred more commonly in the first four days, in women, in lower weight patients, and those receiving higher dosages.
Other cardiovascular side effects have included sinus bradycardia in approximately 0.3% of patients. A rare case of sinus arrest associated with clonidine has been reported. Patients with preexisting sinus node dysfunction, patients who have developed bradycardia while taking other sympatholytic agents, patients who are on another sympatholytic agent, and patients with renal dysfunction are at increased risk of clonidine-associated sinus bradycardia. Clonidine may cause hypertension in some patients with idiopathic orthostatic hypotension, particularly those with autonomic nervous system dysfunction. There have also been reports of congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block, and arrhythmias), palpitations, Raynaud's phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

Allopurinol-induced aseptic meningitis has been reported in two isolated cases where 60-year-old Caucasian men developed high fevers soon after taking an initial dose of 300 mg allopurinol, and when rechallenged, with quick improvement after allopurinol was stopped.
There is a case report of a patient with no history of psychiatric disease whose allopurinol-associated catatonia, rash, and fever responded to steroids.

Allopurinol should be discontinued at the first sign of skin rash or any other signs or symptoms suggestive of a hypersensitivity reaction. In some instances, a skin rash may be followed by more severe adverse reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity, and, rarely, death. Renal dysfunction increases the risk of allopurinol hypersensitivity.

Some patients with preexisting renal disease or poor urate clearance have shown a rise in BUN during allopurinol therapy. Although the mechanism responsible for this has not been determined, patients with impaired renal function should be carefully monitored during the early stages of allopurinol use and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist. Renal failure in association with allopurinol use has been reported among patients with hyperuricemia secondary to neoplastic diseases. Concurrent conditions such as multiple myeloma and congestive myocardial disease were present among those patients whose renal dysfunctionincreased after allopurinol therapy was started. Renal failure is frequently observed with the use of allopurinol therapy. Albuminemia has been observed in patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis. Patients with decreased renal function require lower doses of allopurinol therapy than those with normal renal function. Periodic monitoring of renal function is recommended during the course of therapy.

NOTE: Just because a drug or combination of drugs can cause a
symptom does not mean it is actually causing your symptom. Symptoms can be caused by
medical conditions as well. Make sure that your physician is aware of any symptoms you
are experiencing so he/she can work with you to determine the cause. Please DO NOT STOP
MEDICATIONS without first consulting a physician since doing so could be hazardous to
your health.

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